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Published on: March 29, 2019
Neonatal gene transfer using lentiviral vector for murine Pompe disease: long-term expression and glycogen reduction
S O Kyosen1, S Iizuka, H Kobayashi
1Department of Gene Therapy, Institute of DNA Medicine, The Jikei University School of Medicine, Tokyo, Japan.
Insights
Gene therapy using lentivirus vectors (LV) effectively treated Pompe disease in mice by restoring acid alpha-glucosidase (GAA) enzyme activity. This approach reduced harmful glycogen buildup in muscles and the heart, showing promise for Pompe disease treatment.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- Pompe disease is a genetic disorder caused by deficient acid alpha-glucosidase (GAA) enzyme activity.
- Glycogen accumulation in cardiac and skeletal muscles leads to severe health issues like cardiomyopathy and muscle weakness.
Purpose of the Study:
- To evaluate the feasibility of gene therapy for Pompe disease using a lentivirus vector (LV).
- To assess the efficacy of LV-mediated delivery of human GAA (hGAA) in a mouse model.
Main Methods:
- Newborn GAA knockout mice received intravenous injections of an LV encoding hGAA.
- Transgene expression, GAA activity, and glycogen content were analyzed up to 24 weeks post-treatment.
- Histological analysis and serum hGAA levels were assessed.
Main Results:
- LV injection successfully increased GAA activity and decreased glycogen content in tissues.
- Histological examination confirmed clearance of glycogen storage in skeletal and cardiac muscles.
- Detectable levels of hGAA were found in serum up to 24 weeks, with no significant immune response.
Conclusions:
- LV-mediated gene transfer is an effective strategy for correcting biochemical abnormalities in Pompe disease.
- This gene therapy approach shows potential for further development in Pompe disease mouse models.
Abstract:
Pompe disease results from the deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to accumulated glycogen in the heart and the skeletal muscles, which causes cardiomyopathy and muscle weakness. In this study, we tested the feasibility of gene therapy for Pompe disease using a lentivirus vector (LV). Newborn GAA knockout mice were treated with intravenous injection of LV encoding human GAA (hGAA) through the facial superficial temporal vein. The transgene expression in the tissues was analyzed up to 24 weeks after treatment. Our results showed that the recombinant LV was efficient not only in increasing the GAA activity in tissues but also in decreasing their glycogen content. The examination of histological sections showed clearence of the glycogen storage in skeletal and cardiac muscles 16 and 24 weeks after a single vector injection. Levels of expressed hGAA could be detected in serum of treated animals until 24 weeks. No significant immune reaction to transgene was detected in most treated animals. Therefore, we show that LV-mediated delivery system was effective in correcting the biochemical abnormalities and that this gene transfer system might be suitable for further studies on delivering GAA to Pompe disease mouse models.
